Chang et al. Antimicrobial Resistance and Infection Control (2018) 7:41 https://doi.org/10.1186/s13756-018-0323-3

RESEARCH Open Access Prevalence and antibiotic resistance of isolated from the cerebrospinal fluid of neurosurgical patients at Peking Union Medical College Hospital Jian-bo Chang1†, Hao Wu1†, He Wang2, Bai-tao Ma1, Ren-zhi Wang1 and Jun-ji Wei1*

Abstract Background: Postoperative central nervous system infections (PCNSIs) represent a serious complication, and the timely use of antibiotics guided by the identification of the causative pathogens and their antibiotic sensitivities is essential for treatment. However, there are little data regarding the prevalence of PCNSI pathogens in China. The aim of this study is to investigate the features of pathogens in patients with PCNSIs, which could help clinicians to choose the appropriate empirical antibiotic therapy. Methods: We retrospectively examined the positive CSF cultures in patients who underwent craniotomy between January 2010 and December 2015. We collected data, including demographic characteristics, type of neurosurgery, laboratory data, causative organisms and antimicrobial susceptibility testing results. Results: A total of 62 patients with 90 isolates out of 818 patients with 2433 CSF culture samples were available for data analysis. The estimated incidence and culture-positive rate of PCNSIs were approximately 0.9 and 7.5%, respectively. The predominant organism was coagulase-negative staphylococci, of which most were methicillin-resistant coagulase-negative staphylococci (MRCoNS). All were susceptible to vancomycin, linezolid, rifampicin and amoxicillin-clavulanate. Acinetobacter baumannii was the most frequent causative Gram-negative agent and was resistant to 12 out of 18 antimicrobials tested. The sensitivity rates for tigecycline and minocycline were only 40 and 33%, respectively. Conclusion: PCNSIs could lead to high mortality. Although the MRCoNS were the predominant organism, the management of Acinetobacter baumannii was a major clinical challenge with few effective antimicrobials in PCNSIs. Keywords: Prevalence, Antibiotic resistance, Central nervous system infections, Neurosurgery

Background from 0.3 to 7.8% [2, 3]. The diagnosis of PCNSIs requires a Postoperative central nervous system infections (PCNSIs) high degree of clinical suspicion and lumbar puncture for are relatively rare but serious complication following cerebrospinal fluid (CSF) culture. Once diagnosed, selection neurosurgery, especially craniotomies, resulting in poor of the empirical antibiotic should be guided by knowledge patient outcomes and increasing the total cost of illness. of the causative pathogens and their sensitivities. Craniotomies are used for the treatment of head injury, The epidemiology of bacterial infections varies with time, brain tumor or intracranial hemorrhage, external ventricu- geographical distribution, age, race, underlying medical lar device placement, and entriculostomy [1]. The incidence and/or neurosurgical conditions, means of contraction, of infections after cranial surgery, mostly , varies status of vaccination, and use of antibiotics in the commu- nity [4]. Although the primary pathogens in PCNSI are still * Correspondence: [email protected] † Gram-positive bacteria, such as aureus, Equal contributors there is a possible trend towards greater numbers of Gram- 1Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No.1 negative bacteria, especially Acinetobacter [5, 6]. Another Shuaifuyuan, Dongcheng District, Beijing 100730, China obvious change is the increased rates of multi-antibiotic Full list of author information is available at the end of the article

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chang et al. Antimicrobial Resistance and Infection Control (2018) 7:41 Page 2 of 6

resistant strains such as methicillin-resistant S. aureus the use of antibacterial film, to ensure that there was no (MRSA) and strains that produce extended-spectrum perioperative breach in sterility [17]. We analyzed the β-lactamases (ESBL) in recent years [7]. The potential results of antibiotic susceptibility based on the Clinical underlying cause is the widespread use of empirical and Laboratory Standards Institution (CLSI) methods vancomycin and antipseudomonal β-lactam antibiotics [8]. [15]. Pathogenic organisms were considered resistant if Both the species and the antibiotic resistance profile of they were reported as intermediate or resistant to at bacteria, as well as the blood-brain barrier, are crucial least one of the agents, which included cephalosporins, components to consider when selecting the appropriate fluoroquinolones, aminoglycosides, carbapenems, extended- antibiotics. There have been many recent studies reporting spectrum penicillins, macrolides, and β-lactam/β-lactamase the risk factors for PCNSIs [9–12] in China. Unfortunately, inhibitors. little data regarding prevalence and antibiotic resistance of bacteria have been published. Peking Union Medical Results College Hospital (PUMCH), founded by the Rockefeller From 2010 to 2015, approximately 6500 in-hospital patients Foundation in 1921, is a university general hospital and were treated with approximately 7500 operations in the tertiary referral center in northern China, where the department of neurosurgery. We obtained 2433 CSF department of neurosurgery conducts approximately 1200 culture samples from 818 patients. Of these, 78 patients operations each year. As one of the largest pituitary centers with 108 positive isolates were identified, and their medical in China, about half operations were endonasal trans- records were reviewed. Following review, 12 isolates were sphenoidal approach [13]. Recently, the average length excluded due to contamination, and four patients were of stay has been approximately 6 days. This research removed because they did not undergo surgery. Finally, 62 will report the features of pathogens and investigate the patients with 90 isolates met the inclusion criteria. Of clinical characteristics of post-craniotomy PCNSIs in a them, two patients were failed to obtain the whole medical single institution over the past 6 years. records and the sensitivity results of five isolates were not available. The incidence of PCNSIs was approximately Methods 0.9% (62/6500) and the estimated culture-positive rate of This study was approved by the Ethics Committee of Pe- infection was approximately 7.5% (62/818) and 16 patients king Union Medical College Hospital (PUMCH). The re- with 44 isolates were infected with polymicrobial, in which sults of CSF cultures isolated from inpatients were sixpatientswithmorethantwospecies. reviewed via a computerized log containing records from Table 1 shows the characteristics of 60 patients with posi- January 2010 to December 2015. The data of patients with tive CSF cultures. The median days of hospitalization and positive culture isolates were collected from medical re- the infection period postoperation were 46.5 (IQR = 38) cords using previously designed standardized evaluation days and 9 (IQR = 9) days, respectively. Half of the patients forms (the details showed in Additional file 1)thatincluded underwent surgery using the endonasal trans-sphenoidal demographic characteristics, types of neurosurgery, labora- approach, and most were diagnosed with a pituitary tory data, causative organisms and antimicrobial suscepti- adenoma. Most patients treated with craniotomy were bility testing. The positive CSF culture result was the main diagnosed with occupied lesions. CSF analysis indicated inclusion criteria. The isolation of the same species from that the patients had low CSF glucose and high protein the same patient within 7 days was regarded as the same levels postoperatively. The mortality of culture-positive isolate and not counted multiple times. All the patients met PCNSIs was 8%, which was approximately 16 times greater clinical diagnostic criteria of nervous central infection [14]. than the mortality of inpatients in general (0.49%, 32/6500). Culture contamination was determined by specialists from As Table 2 shows, the distributions of Gram-positive, the clinical laboratory and neurosurgery, which was based Gram-negative and Eumycetes were 56, 40 and 4%, on the identity of the microorganism itself and its clinical respectively. The predominant Gram-positive isolate features [14–16]. Previous cranial operation, including both was coagulase-negative staphylococci (33%), followed elective and emergency procedures, was another inclusion by Enterococcus faecalis (8.9%) and Staphylococcus aureus criteria. Patients who underwent a spinal operation or sim- (7.8%). Acinetobacter spp. was the predominant Gram- ple wound revision without drilled holes were excluded negative organism and was isolated in 16 (17.8%) isolates, from the study. Patients with evidence of concomitant followed by Pseudomonas aeruginosa in 6 (6.7%) and chronic meningitis or encephalitis not due to microbial in- Klebsiella pneumonia in 5 (5.6%). fection were also excluded. Table 3 shows the in vitro antibiotic sensitivities of the All patients received 1.5 g of a second-generation Gram-positive isolates; 24 coagulase-negative staphylo- cephalosporin as prophylactic therapy 1 h before incision cocci isolates were sensitive to linezolid (95%), teicoplanin and followed by a 24-h postoperative course. Strict pre- (100%), vancomycin (100%) and quinupristin-dalfopristin. cautions were taken throughout the operation, including The seven Enterococcus faecalis isolates were all sensitive Chang et al. Antimicrobial Resistance and Infection Control (2018) 7:41 Page 3 of 6

Table 1 Demographic and clinical characteristics of 62 patients to chloramphenicol, cefoxitin, linezolid, nitrofurantoin and with post-neurosurgical bacterial meningitis tigecycline, and the seven Staphylococcus aureus isolates Characteristic Value were all sensitive to amoxicillin-clavulanate, linezolid, Demographic parameters rifampicin, rifampicin, teicoplanin and vancomycin. Of the Mean age (yr) 42.5 Gram-negativeisolates,therewereonlyfivesamplesofthe Acinetobacter spp. available for analysis, and they displayed Sex, male:female 33:29 low sensitivity to tigecycline (40%) and minocycline (33%), Interval between infection and the initial 9 (IQRa =9) neurosurgery (median day) as Table 4 showed. Days in hospital (median) 46.5 (IQR = 38) Discussion Death 5 (8%) PCNSIs are rare but severe complications with heavy disease Operation types burden following cranial operations. They are associated Endonasal trans-sphenoidal approach 28 (45.2%) with increased costs, psychological and emotional trauma Craniotomy 21 (33.9%) and a delay in postoperative adjuvant therapies [9, 12, 18]. Shunt placement 9 (14.5%) The literature contains differing reports of the incidence of PCNSIs. All the PCNSI patients in this study were diag- Decompressive craniectomy 4 (6.4%) nosed by CSF culture, and the incidence was approximately CSF data 0.9% (62/6500), which was similar to some previous studies Leukocyte count (10^6/L) median = 599.5 (IQR = 3573) [3, 19, 20] ranging from 0.3 to 4.8%. However, other studies Glucose level (mmol/L) median = 2.5 (IQR = 1.8) reported higher rates of PCNSIs, ranging from 6.5 to 7.4% Lactate level (mmol/L) median = 119.5 (IQR = 7.5) [9, 12, 21].Onepossibleexplanationmaybethedifferent Protein level (g/L) median = 1.3 (IQR = 2.8) inclusion criteria. In this research, only culture-positive post- operation patients were included, implying a lower false- aIQR interquartile range positive rate. Different types of operations may be another reason for the discrepancy between studies. About half of the patients in this study underwent surgery using the endonasal trans-sphenoidal approach, which tends to have Table 2 Bacteria isolated from cerebrospinal fluid (N = 90) a low incidence of infection of approximately 1–10% [22]. Organism n (%) The culture-positive rate of infection in previous stud- Gram-positive bacteria 51 (56) ies, approximately 50% [9, 12, 21], which was also higher Coagulase-negative staphylococcia 30 (33) than the present study (7.5%). Possible reasons for the lower positive test rate may be the use of cefuroxime as a Enterococcus faecalis 8 (8.9) prophylactic antibiotic and the use of therapeutic antibi- Staphylococcus aureus 7 (7.8) otics as soon as the infection was diagnosed [14]. Another Othersc 6 (6.7) cause could be that the same species of microorganisms Gram-negative bacteria 36 (40) cultured from different isolates within 7 days were Acinetobacter spp.b 16 (17.8) counted as a single isolate. Pseudomonas aeruginosa 6 (6.7) The mortality rate of PCNSIs dropped drastically in past years, from 34% in 2005 [23] to 19% in 2011 [5], Klebsiella pneumoniae 5 (5.6) and a recent study reported that the mortality was 1.8% Enterobacter aerogenes 3 (4) [9]. Compared to the research of Shi [9], the present study Enterobacter cloacae 2 (2.2) showed a higher mortality of PCNSIs (8%). A possible Othersd 4 (4.4) explanation for the higher fatality rate might be that the Eumycetes 3 (4) diagnosis of PCNSIs in this study depended on the isola- Candida albicans 2 (2.2) tion of a pathogen rather than clinical signs, which may mean that many infected patients without positive cultures Cryptococcus neoformans 1 (1.1) were excluded. Underestimating the overall number of aStaphylococcus epidermidis (n = 9), Staphylococcus haemolyticus (n = 5), Staphylococcus capitis (n = 4), Staphylococcus warneri (n = 3), Staphylococcus PCNSIs would lead to overestimating the mortality. Above hominis (n = 3), Staphylococcus sciuri (n = 1), Staphylococcus saprophyticus (n =1) all, the incidence, positive-culture rate and mortality of and other unidentified coagulase-negative staphylococci (n =4) PCNSIs vary between studies and are hard to compare bAcinetobacter baumannii (n = 14). Acinetobacter lwoffii (n = 1), Acinetobacter pittii (n =1) due to different inclusion criteria. cGram-positive organisms: Aerococcus (n = 2), Corynebacterium striatum (n = 2), The predominant organism was Gram-positive bacteria, Streptococcus pneumonia (n =2) dGram-negative organisms: Brevundimonas diminuta (n =1),Escherichia coli (n =1), accounting for approximately 56% of the total isolates. Bordetella Moreno-Lopez (n =1),Serratia marcescens (n =1) Coagulase-negative staphylococci was the major organism, Chang et al. Antimicrobial Resistance and Infection Control (2018) 7:41 Page 4 of 6

Table 3 Gram-positive antibiotic sensitivity rates Organism AMC AMP CLI CHL CIP ERY FOX GEN LNZ LVX NIT PEN RIF SXT TCY TEC TGC VAN OXA QDA Coagulase-negative 33 – 33 – 46 23 40 61 95 57 – 15 86 52 85 100 – 100 25 100 staphylococci [24] Enterococcus faecalis [7] – 67 – 100 75 0 100 67 100 – 100 67 ––20 83 100 83 –– Staphylococcus aureus [7] 100 – 33 – 83 28 83 43 100 ––0 100 50 83 100 100 83 100 AMC amoxicillin-clavulanate, AMP ampiclox, CLI clindamycin, CHL chloramphenicol, CIP ciprofloxacin, ERY erythromycin, FOX cefoxitin, GEN gentamycin, LNZ linezolid, LVX levofloxacin, NIT nitrofurantoin, PEN penicillin, RIF rifampicin, SXT sulfamethoxazole-trimethoprim, TCY tetracycline, TEC teicoplanin, TGC tigecycline, VAN vancomycin, OXA oxacillin, QDA quinupristin-dalfopristin which included Staphylococcus epidermidis, Staphylococcus Of the Gram-negative isolates, only the susceptibility haemolyticus,andStaphylococcus capitis. Acinetobacter of Acinetobacter baumannii was analyzed; the others baumannii was the most frequent causative Gram-negative failed due to lack of isolates. There were 13 patients with agent, accounting for 44% of the total isolates. The micro- 13 Acinetobacter baumannii isolates, and all 13 isolates biological findings in this study were consistent with the were multidrug-resistant (MDR) bacteria with resistance majority of previous results, with the most common organ- to 12 out of 18 antimicrobials tested. Few studies have isms grown in the culture being Gram-positive [10, 23, 24]. reported data on Acinetobacter baumannii isolates from However, in most studies, the dominant Gram-positive CSF, but the SENTRY Antimicrobial Surveillance Program organism is Staphylococcus aureus [23, 24]. Additionally, reported that the frequency of Acinetobacter spp. was ap- Acinetobacter spp. were the most commonly isolated Gram- proximately 7% [31]. However, the MDR rate was amaz- negative bacteria in our study [11, 12, 25, 26], whereas ingly high, ranging from 50 to 70%, and the rate of Enterobacteriaceae were the most common in other studies carbapenem-resistant Acinetobacter baumannii (CRAB) [10, 20, 23, 24]. has risen in recent years [32]. The emergence of MDR Of the coagulase-negative staphylococci, 18 (75%) Acinetobacter baumannii, known as one of the ESKAPE were methicillin-resistant coagulase-negative staphylococci pathogens [33], has become a serious medical problem (MRCoNS), and all were susceptible to vancomycin, teico- worldwide [34, 35]. The data presented here could provide planin and quinupristin-dalfopristin. The results agreed further evidence of the widespread distribution of with the results of previous studies [27, 28]. Approximately multidrug-resistant A. baumannii. This increasing inci- 25% (2 isolates) of Staphylococcus aureus isolates were dence is of great concern considering the lack of treatment methicillin-resistant Staphylococcus aureus (MRSA), and options for dealing with MDR Acinetobacter baumannii these isolates were susceptible to vancomycin, linezolid, infections. Similar to previous study [34], tigecycline and rifampicin and amoxicillin-clavulanate. The incidence of minocycline were the most effective antibiotic for Acineto- MRSA in our study was higher than the 15.7% incidence bacter baumannii, however the sensitivity rates in our Sipahi,O.R.reported[29] and lower than the 40% inci- study were only 40 and 33%, respectively. More studies dencereportedbyRolston,K.V[18]. M.RSA was not a should investigate the treatment strategy in the future. significant problem in our study, as only two samples were Early diagnosis and the timely use of antibiotics are identified. However, it has been a major concern in recent essential for the treatment of PCNSIs [14]. Few studies years [30]. The results of both MRCoNS and MRSA in our from the Chinese mainland about the causative pathogens study indicated that the three most effective antibiotics and their drug sensitivities were available. The present against the MRCoNS were vancomycin, teicoplanin, and li- study not only showed the distribution of pathogens from nezolid. Vancomycin was the last resort and the drug of a region, but reflected a similar trend to that observed choice to treat infections caused by Gram-positive bacteria worldwide, which could help clinicians choose the appro- in CNS infection. Fortunately, all the MRCoNS and MRSA priate empirical antibiotic therapy for PCNSIs. There were were sensitive to it. However, there were two vancomycin- a number of limitations to this study. First, the data did resistant Enterococcus faecalis isolates, therefore, the not yield highly specific information regarding clinical emergence of resistance to vancomycin could be a serious variables, such as the manifestation of CNS infection and concern for PCNSIs. the operative part of encephalic region, and we were not

Table 4 Gram-negative antibiotic sensitivity rates Organism AMK CAZ CIP CRO CSL CTX FEP GEN IPM LVX MEM MNO PIP SAM SXT TCC TGC TZP Acinetobacter spp.b [13]8 0 0 0 170 0 0 180 20330 0 0 0 400 AMK amikacin, CAZ ceftazidime, CIP ciprofloxacin, CRO ceftriaxone, CSL cefoperazone-sulbactam, CTX cefotaxime, FEP cefepime, GEN gentamycin, IPM imipenem, LVX levofloxacin, MEM meropenem, MNO minocycline, PIP piperacillin, SAM ampicillin-sulbactam, SXT sulfamethoxazole-trimethoprim, TCC piperacillin-clavulanate, TGC tigecycline, TZP piperacillin-tazobactam Chang et al. Antimicrobial Resistance and Infection Control (2018) 7:41 Page 5 of 6

able to provide insight with regards to these topics. Laboratory Medicine, Peking Union Medical College Hospital, Peking Union Second, although the number of isolates in the present Medical College, Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Dongcheng District, Beijing 100730, China. study was larger than some of previous [10, 11, 24, 34], there was still selection bias, and data from a single insti- Received: 20 July 2017 Accepted: 20 February 2018 tution may not be representative of the entire population of China. Finally, the resistance feature of each isolate was not investigated at the molecular level. References 1. Ottenhausen M, Bodhinayake I, Evins AI, Banu M, Boockvar JA, Bernardo A. Conclusion Expanding the borders: the evolution of neurosurgical approaches. Neurosurg Focus. 2014;36(4):E11. Postoperative central nervous system infections (PCNSIs) 2. 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